N-heterocyclic thioureas as anthelmintic agents

ABSTRACT

New thio ureas in which a p-phenoxyphenyl, p-phenylthio-phenyl or p-phenylaminophenyl radical is attached to one nitrogen atom and which are substituted at the other nitrogen atom either by two lower alkyl groups or a polymethylene bridging member of 2 to 6 carbon atoms, whereby one of the methylene groups can be replaced by an optionally substituted imino group, processes for the production of the new compounds and compositions containing these compounds.

United States Patent Spaun et al.

N-HETEROCYCLIC THIOUREAS AS ANTHELMINTIC AGENTS lnventors: Ruediger Spaun, Bottmingen; Alain Claude Rochat, Birsfelden; Jean-Jacques Gallay, Magden; Paul Brenneisen, Basel, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,

Filed: Oct. 11, 1973 Appl. NO.I 405,614

Related US. Application Data Division of Ser. No. 175,723, Aug. 27, 1971, Pat. No. 3,781,290.

Foreign Application Priority Data Sept. 2, 1970 Switzerland 13lll/7O Dec. 23, 1970 Switzerland 19065/70 US. Cl. 424/250; 424/244; 424/267;

424/274; 424/322 lnt. Cl A6lk 27/00 Field of Search 424/250, 267, 322;

[ Aug. 5, 1975 [56] References Cited UNITED STATES PATENTS 3,719,702 3/1973 Traber et al. 424/250 3,781,290 12/1973 Spaun et al. 424/322 Primary E.\'aminerV. D. Turner Attorney, Agent, or FirmFrederick H. Rabin [57] I ABSTRACT l2 Claims, No Drawings N-HETEROCYCLIC THIOUREAS AS ANTHELMINTIC AGENTS This is a division of application Ser. No. 175,723, filed on Aug. 27, 1971 now US. Pat. No. 3,781,290.

The present invention relates to new thio ureas, a process for the manufacture of these compounds and their use for combating parasitic Helminths.

According to the present invention there are provided thio ureas of general formula I:

in which R is hydrogen, halogen, hydroxyl, nitro, carboxyl, low alkyl, low alkoxy, alkoxycarbonyl, low alkylthio, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino or sulfamoyl, R is hydrogen, halogen, nitro or low alkyl, alkoxycarbonyl or carboxyl, R is hydrogen, halogen, nitro or carboxyl, and R and R are each low alkyl or together are a polymethylene bridge having 2 to 6 carbon atoms, wherein one methylene group can be replaced by the group N-R in which R is hydrogen, low alkyl or hydroxyalkyl, phenyl or benzyl, and X is oxygen, sulphur, sulfonyl or imino (NH).

ln this formula, by low alkyl for R R R and R there are to be understood straight or branched-chain alkyl groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, or one of the foru isomeric butyl groups. Such alkyl groups also form the alkyl part of R when that is alkoxy, alkylthio, alkylamino, dialkylamino, or alkoxy carbonyl. Low alkanoyl groups such as acetyl, propionyl, butyryl, valeryl, isobutyryl, are to be understood as acyl substitutes of an acyl amino group R Any heterocyclic group formed by groups R, and R and the neighbouring nitrogen atom preferably has 5-7 ring members. Such heterocycles are, for example, pyrrolidine, piperidine, hexahydroazepine, piperazine, N-methyl-piperazine and N-phenyl-piperazine. The group R by which the heterocycles with 2 nitrogen atoms can be substituted has the same meanings when low alkyl as given above for R R R and R By halogen, fluorine, chlorine, bromine and iodine are to be understood, chlorine and bromine being preferred.

The new thio ureas of fonnulal are manufactured according to the invention by reacting an iso-thiocyanate of formula 11:

R" 4' TH/ (III) in which R, and R' are each low alkyl or form together a polymethylene bridge having 3 to 6 carbon atoms, wherein one of the methylene groups can be replaced by the group NR' in which R is a low alkyl group, hydroxyalkyl group, phenyl group, benzyl group, or a low alkoxycarbonyl group, and if desired transforming compounds obtained in which R is a nitro group by reduction and compounds in which R is an acylamino or alkoxycarbonyl amino group and/or compounds in which R is an alkoxycarbonyl amino group by hydrolysis into compounds of formula I in which R is the amino group and/or R is hydrogen. The hydrolytic splitting off of low alkoxy carbonyl groups or acyl groups takes place preferably in alkali medium, for example by warming the compound obtained in aqueous alkali metal hydroxide solution.

The reaction is advantageously carried out at room temperature or slightly elevated temperature in an inert solvent. As solvents are suitable, for example, aromatic hydrocarbons, for instance benzene, toluene, or aliphatic or aromatic halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, as well as ether and ether compounds such as diethyl ether and dioxane, as well as N-alkylated acid amides such as dimethyl formamide as well as mixtures of the solvents with one another, also water or mixtures of the solvents with water.

The isothiocyanates of the formula 11 used as starting materials can be obtained according to known methods, for example by reaction of amines of the general formula IV R x g} N112 I R2 R, (IV) wherein R R R and X have the meaning given under formula I, with thiophosgene. (c.f. Swiss Pat. No. 470,846 and Belgian Pat. No. 736,010).

The new thio ureas of formula I can also be obtained by reacting a thiocarbamicacid-derivative of formula V:

with an amine of formula III and if desired converting compounds obtained in which R, is a nitro group by reduction and compounds by which R, is an acylamino or alkoxycarbonyl amino group and/or compounds in which R is an alkoxycarbonyl amino group by hydrolysis into compounds of formula 1 in which R, is the amino group and/or R is hydrogen. The reaction is carried out advantageously at room temperature or slightly elevated temperature in an inert solvent. Suitable inert solvents are, for example aromatic hydrocarbons, for instance benzene, toluene, or aliphatic or aromatic halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene, as well as ether and ether compounds, as well as N-alkylated acid amides such as dimethyl formamide as well as mixtures of the solvents with one another, also water or mixtures of the solvents with water.

The starting materials of the general formula V can be obtained by reacting an amine of the general formula IV with a halothiocarboxylic acid O-phenylester in the presence of an acid binding agent. As acid binding agents there are preferably used tertiary amines such as trialkylamine, pyridine bases etc., also hydroxides and carbonates of alkali and alkaline earth metals.

A further process for the manufacture of the novel thio ureas of formula 1 consists in reacting an acylated amine of formula VI:

in which R is an acyl group easily removable by hydrolysis, with a thio carbamoyl halide of formula VII:

*-.1-s-N"' a. he (Val) in which Hal is chlorine or bromine in the presence of an acid binding agent and alkaline hydrolysing the resulting thio urea to remove the acyl group R and if desired transforming compounds'obtained in which R, is a nitro group by reduction and compounds in which R is an acyl amino or alkoxycarbonyl amino group and/or compounds in which R" is an alkoxy carbonyl amino group by hydrolysis into compounds of formula I in which R is the amino group and/or R is hydrogen. ln 1 chlorobenzene, as well as ether and ether compounds such as diethyl ether and dioxane, as well as N- alkylated acid amides such as dimethylformamide as well as mixtures of the solvents with one another, also water or mixtures of the solvents with water.

The starting materials of the formula VI are obtained according to known methods by alkylation of amines of the formula IV.

Suitable easily split off groups R by hydrolysis are the trifluoroacetyl group and the tertiarybutoxycarbonyl group. For the alkaline hydrolysis, preferably inorganic bases such as alkali metal hydroxides are used. As acid binding agent, particularly tertiary amines may be used, for example trialkylamine but also inorganic bases such as hydroxides and carbonates of alkali and alkaline earth metals may be used. Additionally, for this reaction amines of formula IV can be used which are acylated a carbobenzoxygroup, in those cases where R and R are not nitro. The carbobenzoxy group is then removed, by hydrogenolysis with catalytic hydrogen. v

The new thio ureas of formula I in which one of symbols R, and R means a group which is able to form salts, eg an alkyl or a dialkyl amino group or the carboxyl group, can be transformed into the corresponding salt with acids or bases which are nontoxic for human and animal organisms. As acids both inorganic and organic acids are of value, for example, hydrohalic acids, sulphuric acid, phosphoric acids, acetic acid, aminoacetic acid, butyric acid, lauric acid, stearic acid, oxalic acid, adipic acid, maleic acid, tartaric acid, lactic acid, methanesulphonic acid, p-toluenesulphonic acid, etc. As bases there should benoted particularly alkaline and alkaline earth metal hydroxides and alkanolates, as well as quaternary ammonium bases and ammonium salts.

For the manufacture of quaternary ammonium salts, the new thio ureas of formula I in which R is a dialkyl amino group can be transformed into the corresponding ammonium salts by conventional quatemisation agents such as alkyl halides, dialkyl sulphates, toluene sulphonic acid esters, etc. If the anion of the quaternary salt obtained is toxic for human and animals, then it can be exchanged by reaction with a non-toxic acid for a non-toxic anion.

The following examples will illustrate the manufacture of novel thioureas of formula I. The subsequent table shows further thio ureas which can be manufactured using the process of the example. Temperatures given are in C throughout.

EXAMPLE i A solution of 10 g 4-nitro-4'-isothiocyanodiphenylamine in ml toluene was treated at a temperature of 50 with stirring with a solution of 6.3 ml dibutylamine in 20 ml toluene. After 3 hours stirring at 50 the solution was filtered from the precipitate obtained. By recrystallising the crude product from methanol 10.9 g N-[4-(4'-nitroanilino)phenyl]-N',N- dibutylthio urea of melting point l79183 were. obtained.

EXAMPLE 2 A solution of 4 g N-[4-phenoxyphenyl]-thiocarbamic acid-O-phenyl ester in 50 mltoluene was reacted at a 7 chloride formed wa sjfi'ltered offand the filtrate was evaporated to dr'ynes n ,vacuokjFor removal of the'trifluoroacetylig'roup 'th 'dc product was dissolved in hot benzeneland boiledundcrireflux in the'presence of 1' g powdered K( )l*l' for'll hours. The benzenesolution was washed with'watcr; dried over potash, filtered and evaporated off. .'l'h' e.;'re s idue was 7 recrystallised from ethanol; 1.8,;g N-'[.4-(4@n'itrophenoxy-Fphenyl]-N',N'- diethyl'thio: 13s-1'40., H

Further compound lowing table ned are shown in the fol- I-u'ra was obtained of melting point Continued Compound Melting point (C) or refractive index N-l4-(4'-Chloranilino)-phenyl1- N'-methyl-N'-propylthio urea -138 N-[4-(4-Nitroanilino)-phenyll- N-methyl-N'-propylthio urea 159-161 N-[ 4( 4'-Hydroxyanilino )-phenyl N,N'-diethylthio urea 72-76 N-[ 4-( 3'.4'-Dimethylanilino )-phenyl N'-ethyl-N'-sechutylthio urea 95-100 N-l4-(4'-Methoxyanilin0)-phenyll- N'-ethyl-N-sec-butyltl1io urea 80-84 N-[ 4-( 3 -Methoxyanilino )-phcnyl N'.N'-diethylthio urea 134-140 4Methoxy-4'-( N-methylpiperazinyl thiocarbonylamino-diphenylether 138-140 4-Mcthyl-4'-( N-methylpiperazinyl )-thiocarhonylamino-diphenylether 134-137 4-Nitro-4'-( N-methylpiperazinyl )-thiocarbonylamino-diphenylether 168-169 4-Brom4'-(N-methylpi erazinyl)-thiocurbonylamino-dipheny ether 151-152 4-Melhylthio-4'-( N-methylpiperazinyl thiocarbonylamino-diphenylamine 164-166 4-Methyl4'-( N-methylpiperazinyl )-thiocarbonylamino-diphenylamine -152 4-Chlor-4' N-methylpiperazinyl )-thiocarbonylumino-diphenylamine 165-167 4-Nitro-4-( N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 191-196 4-Chlor-3 '-carboxy-4'-( N-methylpiperazinyl )-thiocarbonylamino-diphcnylamine 188-190 4-nitro-4-N-phenylpiperazinyl )thiocurbonylamino-diphcnylether 183-88 4-( n-methylpiperazinyl )thiocarbonylamino-diphenylether 138-42 4-( n-phenylpiperazinyl l-thiocarbonylamino-diphenylether -73 4-nilro-4-( n-ethoxycarbonylpiperazinyl thiocarbonylamino-diphcnylether 185-88 4-nitro-4'-( N-hydroxyethylpiperazinyl thiocarbonylamino-diphenylether 165-67 4-( N-hydroxyethylpipcrazinyl )-thiocarbonylamino-diphenylether 1 37-40 2.4-dinitro-4'-( N-methylpiperazinyl thiocarbonylaminodiphenylether 197-99 4-brom0-4'-( N-ethoxycarbonylpiperazinyl thiocarbonylamino-diphenylether 140-44 4-nitro-4'-( N-ethylpiperazinyl )-thiocarbonylamino-diphenylether 1 59-63 4-methoxy-4 N-ethylpiperazinyl )-thiocarbonylamino-diphenylether 138-40 4-nitro-4'( N-propylpiperazinyl )-thio carhonylamino-diphenylether 1 49-50 4-nitro-4-( N-butylpiperazinyl )-thiocarbonylamino-diphenylether 1 24-26 4 N-i-propylpiperazinyl )-thiocarbonylamino-diphenylether 1 30-33 4-nitro-4'-( N-i-propylpiperazinyl )-thiocarbonylamino-diphenylether 1 55-58 4-nitro-4'-( N-phenylpiperazinyl )-thio carbonylamino-diphenylamine 235-40 4-methylthio-4 N-phenylpiperazinyl thiocarbonylamino-diphenylamine 1 75-80 4-nitro-4'-( N-hydroxyethylpiperazinyl thiocarbonylamino-diphenylamine -200 Z,4-dimethyl-4-( N-ethylpiperazinyl thiocarbonylamino-diphenylamine 167-71 The new thio ureas of formula 1 are suitable for combating parasitic helminths and their stages of development. Among the endo-parasites which attack domestic and useful animals, parasitic helminths are particularly dangerous pests. Thus it is often the case with attacked animals that there is both a retarded growth and disease is released by the helminth attack which the animals die from. It is thus of the greatest importance to develop agents which on the one hand will prophylactically hinder the attack by such endo-parasites, but which on the other hand will also have a good anthelmintic action with a broad spectrum of activity. Previously known ureas and thio ureas with anthelmintic action have not heretofore been satisfactory because in compatible doses they have insufficient action while in therapeutically active doses they show undesirable side effects or alternatively have too narrow a spectrum of activity.

Ureas such as 3,5-bis-trifluoromethyl-4'- nitrodiphenyl urea and 3,5,3'-tris-trifluoromethyldiphenyl urea (both compounds included in Belgian Pat. No. 616,735, the first in the examples thereof) also show good activity but in the concentrations required to be used, show also a strong irritant activity, which leads to extremely thin liquid droppings in hens and diarrhoea in sheep and horses. Thus, for example, the thio ureas known from British Patent Specification 956,520, the 3,3',5-tris-trifluoromethyldiphenylthio urea and the N-( 3,5-bis-trifluoromethylphenyl)-N'-(3'- chlorophenyl ).-thio urea show no action at a concentration of a 100 mg per kg body weight against Ascaridia galli in hens and enterobius in mice, while giving substantial toxic side effects at 500 mg/kg body weight.

The thio ureas of formula 1 according to the invention are not toxic in normal use cm centrations (compare the following tests). They are very compatible matidae), cestodes (e.g. Taeniidae, Anoplocephalidae,

Hymenolepidae) and trematodes (e.g. Fasciolidae) in domestic and useful animals such as cattle, sheep, goats, horses, pigs, cats, dogs and birds.

Of particular value on the basis of their good compatability and activity are thio ureas of formula la cs it in which R is halogen, particularly chlorine, nitroor a low alkyl group, X is oxygen, sulphur or the imino group (NH) and R and R have the meaning given under formula I, particularly those in which R and R together with the nitrogen atom to which they are bonded, form an N-substituted piperazine group.

The new active agents can be used in the form of solutions, emulsions, suspensions, drenches, powders, tablets, boluses, and capsules and can be administered per orally or abomasally to the animals directly, either in a single dose or the dose can be repeated. In most cases, better effect is obtained by protracted administration but results can be obtained with smaller total doses. The active agent or mixtures containing it can also be added to the food or drink for the animals or it can be contained in so-called food premixes.

For preparing application forms, it is customary to use solid carrier materials for example, kaolin, talcum, bentonite, cooking salt, calcium phosphate, carbohydrates, cellulose powder, cotton seed meal, carbowaxes, gelatine, or liquids such as water, optionally with the addition of surface active agents such as ionic or nonionic dispersing agents as well as oils or other solvents which are not harmful to the animal organisms. If the anthelmintic agent is to be in the form of a food concentrate, then as carrier materials there may tein concentrates. Such food concentrates can contain apart from the active agent of this invention, other additives such as vitamins, anti-biotics, chemotherapeutic agents, bacteriostatic agents, fungistatic agents, coccidostatic agents, hormone preparations, materials with anabolic action or other materials which improve growth or influence the quality of the meat of the slaughtered animal or substances which are useful for the animal in other ways.

Suitable dose forms for oral administration such as dragees and tablets preferably contain 100 500 mg of the active substance according to the invention and indeed, 20-80% of a compound of the general formula I. For their manufacture the active substance may be combined e.g. with solid powder carrier materials such as lactose, saccharose, sorbitol, mannitol, starches such as potato stach, maize starch or amylo pectin, or laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, and formed to tablets or dragee cores. The latter is preferably coated for example with concentrated su'gar solution which, for example, can contain gum arabic, talc and/or titanium dioxide, or they can be coated with a laquer dissolved in a highly volatile organic solvent or organic solvent mix. These coatings can also include dyes or pigments in order to be able to characterize various doses of active substance optically.

Determination of anthelmintic action in hens which were infested with Ascaridia galli 13 day old chicks were artificially infested with eggs of Ascaridia galli (helminths). Groups of 5 hens each were used per test. weeks after infestation, the active substance was administered to the animals in 1 dose per day on 3 subsequent days. As control infested hens which were not medicated were used. Evaluation:

The number of Ascaridia galli excreted per test group over the course of 5 days after the first administration of the active substances was determined daily and the number still present in the gut on the 5th test day was also determined by section. Additionally, the number of worm-free hens was determined.

be used p gy foods, p foods P 45 Results are shown in the following table.

No. of Ascaridia galli of 5 hens Daily dose Excreted during Active Substance mg/kg the period No. of

body weight of test found on worm-free General 3 absolute 7c of total sectioning hens Conditions No. number 4-[4-(4'-Nitrophenoxy)-phenyl]-N'N'- 750 63 O 5 good diethylthio urea N-[4-(4'-Nitrophenoxy)-phenyl]- N'N-dipropylthio 750 47 I00 0 5 good urea N-[4-(4-Nitrophenoxy)-phenyl]-N'N- 750 83 I00 0 5 good dibutylthio urea N-l4-(4'-Chlor-3- methylphenoxyphenyl ]-N 'N '-diethyl- 750 30 83 6 4 good thio urea N-[4-(4'-Nitrophenoxy )-phenyl ]-NN'- 750 6() 100 0 5 good dihexylthio urea N-[4-(4'-Nitrophe noxy)-phenyl]-N'- methyl-N'-propyl- 750 58 l()() (l 5 good thio urea C ontmued No. of Ascaridia galli of 5 hens Daily dose Excreted during Active Substance mg/kg the period No of 7 body weight of test found on wormfree General absolute 7c of total sectioning hens Conditions Nor number N-[ 4 4'-Chlorphenoxy )-phcnyl ]-N'N- 750 12 100 good dibutylthio urea N-l4-(4' Methoxy hcnox hen 'l i lethyl N sec. I 750 ll 91 l 4 good butylthio urea N-[ 4-( 4'-Nitrophenoxy)-phenyl]-N'- ethyl-N-sec.butyl- 750 g lOO 5 d thio urea N-[4-(4-Bromanilino )-phenyl ]N'- I N'-diethylthio 750 100 0 5 good urea N-[4-(3'4'-Dimethylanilino )-phenyl ]-N'N'- 750 124 93 6 4 good diethylthio urea N[4 (4-Methoxyanilino )-3-carhoxyphenyl 750 l04 100 O 5 good N'N-diethylthio urea N-[4-(4'-Nitroanilino)- phenyl ]-N'N'-dihexyl- 750 43 100 O 5 good thio urea N-[ 4-( 3'4' Dimethylanilino )-phenyl ]-N-elhyl- 750 6 l 4 good N'-sec.butylthio urea 4-Methoxy-4'-( N-methylpiperazinyl )-thiocarho- 750 125 I00 0 5 good nylamino-diphenylether 4-Nitro-4'-( Nmethylpiperazinyl )-thiocarbonyl- 750 l 25 100 0 5 good aminodiphen vlether 4-Methylthio-4'-( N-methylpiperazinyl )-thiocarbonylamino-diphenyl- 750 83 4 3 good amine Y 4-ethyl-4'-( N-methylpiperazinyl )-thiocarbonyl- 750 191 0 3 good amino-diphenylamine 4-Chlor-4'-(N-methylpiperazinyl )-thiocar honylamino-diphenyl- 750 I36 100 0 5 good amine Tests on rats infected with Fasciola hepalica White laboratory rats were artificially infected with liver leeches (F asciola hepaticu). After expiry of the preparation time the attack of the rats by liver leech was determined by 3 independent droppings analyses. For the test, groups of 4 attacked rats were treated with the active substance in the form of a suspension applied via a stomach probe on 3 subsequent days, once daily. In the 3-5 week after administration of the active substance a weekly droppings analysis was carried out on the content of liver leech eggs. At the end of 5 weeks from the start of the test, the test animals were killed and the presence of any liver leeches was determined. Results are shown in the following table.

droppings control No. of Daily dose of egg excretion liver Active Substance in mg/kg 3 times leeches General body weight before after after Condition medication medication section N-[4-(4-Nitrophenoxy)- phenyl I-N 'N'-dimethyl- 200 positive negative 0-0-0-0 good lhlO urea N-[ 4-( 4'-Nitrophcnoxy phenyl I-N N '-diethylthio 200 0-0-0-0 good urea N-l4(4-Nitrophenoxy)- phenyl ]-N 'N -Llipropylthio- 200 ()-0-0-0 good urea N-[ 4-( 4'-Chlorphenoxy phenyl l-N N-diethy]thio l 50 ()--()()2 good urea N-l4-(4'-Nitrophenoxy)- phenyl l-N'N '-dibutylthio 200 ()-()-()0 good urea N-[ 4-( 4'-Nitrophcnoxy Z-chlorphenyl ]-N N-di- 200 5-()-()-() good cthylthio urea N-[4-(4'-Nitrophenox 3-chlorphenyl]-N'N- i- 200 ()-()-()-0 good ethylthio urea N-l4-(4'-Chlorphenoxy)- 3-caboxyphenyl ]-N' N'- 200 ()0--()() good diethylthio urea Active Substance NI 4-( 4'-Nitrophenoxy phenyl ]-N 'N '-pentz1- methylenthio urea thio urea N-[4-(4'-Nitrophenoxy) phenyl]-N-methyl-N- ethylthio urea N-l4-(4-Bromphenoxy -phenoxy)-phenyl]-N'N-dihexylthio urea N-[ 4-( 4'-Nitrophenylthio phenyl ]-N 'N '-diethylthio urea N-[4-(4'-Methylanilino)- phenyl1-N 'N -diethylthio urea N-[ 4-( 4-Chlorphenylthio phenyl ]-N 'N '-diethylthio urea N-[4-(4'-Chlorphenylthio)- 3-carboxyphenyl1-N'N -dimethylthio urea N-[4-(4'-N,N-Dimethylaminoanilino )-phenyl N'N'-dibutylthio urea N-[4-( 4-Nitrophenoxy)- phenyl]-N-ethyl-N'-sec. butylthio urea N-[4-(4-Methylphenoxy)- phenyl ]-N 'N '-diethylthio urea 4-Methoxy-4'-(N-methylpiperazinyl )-thiocarbonylamino-diphenylether 4-Methylthio-4'-(N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 4-Ethyl-4'-(N-methylpiperazinyl )-thiocarbonylamino-diphenylamine 4-Chlor-4 N-methylpiperaziny] )-thiocarbonylamino-diphenylamine Tests on mice infected with Hymenolepis nana The active substance was administered to white mice in the form of a suspension by means of a stomach probe, the white mice being artificially infected with Hymenolepis nana. Five animals were used per test.- Each group of animals had the active substance administered once daily for 3 subsequent days. The animals Continued Daily dose in mg/kg body weight No. of

leeches before after after medication medication section o-o-o-o A General Condition good good

' good good good

. good good good

good

good

good

good

good

good

good

good

good

were killed 8 days after the 45 sectioned.

Evaluation after section 0 place bycounting the number of ringworms found in the gut. As control, untreated but similarly and simultaneously infected mice were used. The agent was re 50 ceived by the mice without any symptoms. Results are shown in the following table; A

beginning of treatment and l the test animals took zinyl )-thiocurhonyluminodiphenyluminc Daily dose Attack of Action on Active Agents mg/kg I 5 test control body weight animals on animals on I section section N-[ 4-( 4-Chlorphenoxy )-phenyl t N'N'-diethylthio urea 750 0-0-()-()-() 3-4-15-[8-19 N-[4-(4'-Nitrobenoxy)-phenyl]- I N'N'-dibutylthio urea 750 0-0-0-0-0 1-8-1 1-20-39 N-[4-(4'-Methylphenylthio)- I phenyl]-N'N-diethylthio urea 750 0-0-0-3-4 1-2-3-4-5 I N-[4-(4'-Chlorphenylthio)- g phenyl]-N'N'-diethylthio urea 75() 0-0-0-0-0 2-2-7-8-8 N-l4-(4-Chloranilino)-penyllv v N'N-dicthylthio urea 750 .O-O-O-O-l 0-1-2-2-4 N-[4-Anilinophenyl]-N'N-div t I cthylthio urea 750 0-0-0-4-5 1-2-3-4-5 4-Nitro-4'-(N-methylpipcrazinyl-umino-diphenylether 7S0 0-0-0-1-1 04-13-13-123 4-Mcthylthio-4'-(N-mcthyl- I pipcrazinyl)-thiocarbonyl- 750 ()()-()--()0 l 1-] 3-16-23-32 umino-diphenylumine' 1 4-Chlor-4'-(N-mcthylpipcra- I I t Tests on mice infected with Enterobius The active substance was administered in the form of a suspension to white mice via a stomach probe, the mice having previously been infected with mouse En- 1.0 parts carboxymethyl cellulose 46.8 parts water 30 parts N-[4-( 4 '-chloro-3 '-methylphenoxy phenyl]N'N'-diethylthio urea terobius. Five animals were used per test. Each group 5 70 parts anut oil of animals had the active substance administered for 3 Th a ti b tan e were milled together to the finsubsequent days, Once daily. est possible particle size (5l0 microns) together with The daily dose per animal was 750 mg active subcarriers, distribution agents and other additives. The Stance P kg of y weight resulting homogeneous concentrates were adminis- Oh the 6th y after the beginning of the treatment, 10 tered to domestic and useful animals by means of a the animals were killed and sectioned. The evaluation d hi i L Th e tr te were used for the took Place after Section of the test animals y counting temporary deworming of a number of farm animals, for the number of mouse Enterobius in the gut. Similarly example, f deworming a fl k of sheep attacked by infected by untreated mice served as control. Haemonchus Sppq Tri hostrongylus spp. etc.

The agent was affected by the mice without sympp d Concentrate; toms. Results are expressed in the following table. For the f t re f an 50% d (b) In this table powder concentrate the following materials were animal dead used:

1 adult form a. parts N-[4-(4-nitrophenoxy)-phenyl]-N'N- 1 juvenile form. 20 diethylthio urea Daily dosage attack of attack of control Active Substance mg/kg 5 test animals on body weight animals on section section N-[ 4-( 4'-Chlorphenoxy )phenyl]-N'N-diethylthio urea 750 OOO-OO 8/Ll-8/Ll-l4/L1- l5/Ll-20/Ll N-[4-(4-Nitrophenoxy)- 750 0-0-0-0-0 lO/l-l2/ll3/Ll phenyl l-N N-dibutylthio 16/L l-20/l urea N-[4-(4-Methoxyphenoxy 750 O-O-O-l-Z/l 3-5/L l-6/L l-7/ phenyl ]-N 'N-dimethylthio l-8/L1 urea N-[ 4- 4-Nitrophenoxy 750 0-0-0-2-2 4/L1 1 3/Ll-15/L- phenyl ]-N 'N -ethylenthio 18/1. l-20/Ll urea N-[4-(4-Methoxyphenoxy)- 750 O-0-l-2/L3 +2-3/L4/L1- phenyl]-N'N'-dibutylthio l2/Ll urea N-[4-(4'-Bromphenoxy)- 750 0-0-0-0/1-1/1 +-2-3/L-4/L1- phenyl l-N 'N-dihexylthio l2/Ll 1'23 N-[4-(4'-Chloranilino)- 750 0-O-O-O0 IO/Ll-lZ/Ll-l6/ phenyl l-N 'N-diethylthio L l-20/ L l-24/ L l urea N-l4-(4-ethyla.nilino)- 750 0-0-0- 0/l-3/Ll 2/Ll5/Ll6/Ll Phenyl l-N 'N'-diethylthio 8/L ll 2/L l urea N-[4-( 4-Methylanilin0 750 O-(J-O-O-O lO/l-l2/ l-l 3/L lphenyl ]-N N '-diethylthio l 6/ L l-ZO/l urea 4-Methoxy-4-(N-methyl- 750 O0OO/2/2-O/2/3 3/ l/ l-3/2/3-7/ piperazinyl )-thiocarbonyl- 3/ L-8/ 8/4- 1 9/4/ 8 umino-diphenylether 4-Nitro-4-( N-methylpipera- 750 O-()-- ll l L-3 5/9/86/5/59/ zinyl )-thiocarbonylamino- 9/10-13/2/2-20/ diphenylether lO/9 4-Methylthio-4-( N-methyl- 750 0-0-0-0-0 5/4/4-6/ 3/ 3 10/ pipcrazinyl )-thiocarbonyl- 5/4-12/12/10-17/ aminn-diphenylamine 4-ethyl-4-(N-methylpipera- 75o l/3L-0-00-0/l 3/1/13/2/3-7/ zinyl )-thiocarbonylamino- 3L-8/ 8/4- 19/4/ 8 diphenylamine 4-Chlor-4'-( N-methylpipera- 750 l-O-O-O-O 3/ l l3/2/37/3L zinyl)-thiocarbonylamin0- 8/8/4-19/4/8 diphenylumine In the following use forms of the new thio ureas of 3 parts polyoxygethylene sorbitan monoolea te general formula I are described. Parts given are parts 3 parts ligninsulphonic acid sodium salt by weight. 44 parts Bolus alba Pasty active substance concentrates: b. 25 parts N-[4-(4'-chlorophenoxy)-phenyl]-N'N'- Such semi-solid or oily active substance concentrates diethylthio urea have, for example, the following composition: 3 parts polyvinylpyrrolidone a. 40 parts N-[4-(4-nitrophenoxy)-phenyl]-NN- 3 parts dodecylbenzene sulphonate dibutylthio urea 39 parts Kieselguhr 10 parts Bolus alba 2 parts sodium lignosulphonate 0.2 parts sodium benzoate 30 parts Bolus alba The active substances given were, for example, coated onto the carrier material as an acetonic solux-Qrm-cs-m l to 4 carbon atoms, X is oxygen, sulfur or imino; and R is alkyl of from 1 to 4 carbon atoms, hydroxyalkyl of from 1 to 4 carbon atoms, phenyl or benzyl; and (2) a carrier.

wherein R is hydrogen, chlorine, bromine, alkyl of from 1 to 4 carbon atoms, alkylthio of from 1 to 4 carbon atoms or alkoxy of from 1 to 4 carbon atoms; R

is hydrogen, alkyl of from 1 to 4 carbon atoms or nitro-; X is oxygen, sulfur or imino; and R is alkyl of from 1 to 4 carbon atoms, phenyl, hydroxyalkyl of from I to 4 carbon atoms or ethoxycarbonyl.

5 A method according to claim 4 in which R, is hydrogen, chlorine, bromine, alkyl of from 1 to 4 carbon atoms or alkoxy of from l to 4 carbon atoms; R is hydrogen; and X is oxygen.

6. The method according to claim 5 in which the compound is 4-Methoxy-4'-(N-methylpiperazinyl)- wherein R is chlorine, bromine, nitro or alkoxy of from 20 thiocarbonylaminodiphenylether.

7. The method according to claim 5 in which the compound is 4-Nitro-4'-( N-methylpiperazinyl)- thiocarbonylaminodiphenylether.

8. A method according to claim 4 in which R is hy- 2. An anthelmintic composition comprising l as ac- 25 drogen, Chlorine, bromine, lky 0f 1 t0 4 Car n tive ingredient an anthelmintically effective amount of a compound of the formula wherein R is hydrogen, chlorine, bromine, alkyl of from 1 to 4 carbon atoms, alkylthio of from 1 to 4 carbon atoms or alkoxy of from l to 4 carbon atoms; R is hydrogen, alkyl of from l to 4 carbon atoms or nitro; X is oxygen, sulfur or imino; and R is alkyl of from 1 to 4 carbon atoms, phenyl, hydroxyalkyl of from 1 to 4 carbon atoms or ethoxycarbonyl; and (2) a carrier.

3. A method for combatting parasitic helminths which comprises administering to an animal suffering from the effects of said helminths an anthelmintically 45 effective amount of a compound of the formula wherein R is chlorine, bromine, nitroor alkoxy of from 1 to 4 carbon atoms, X is oxygen, sulfur or imino; and R is alkyl of from 1 to 4 carbon atoms. hydroxyalkyl of from 1 to 4 carbon atoms, phenyl or benzyl.

4. A method for combatting parasitic helminths which comprises applying to an animal suffering from the effects of said helminths an anthelmintically effective amount of a compound of the formula atoms or alkylthio of from 1 to 4 carbon atoms; R is hydrogen; X is imino; and R is alkyl of from l to 4 carbon atoms, phenyl or hydroxyalkyl of from 1 to 4 carbon atoms.

9. The method according to claim 8 in which the compound is 4-Methylthio4'-(N-methylpiperazinyl)- 40 thiocarbonylamino-diphenylamine.

10. The method according to claim 8 in which the compound is 4-ethyl-4'(N-methylpiperazinyl)-thiocarbonylaminodiphenylamine.

11. The method according to claim 8 in which the compound is 4-Chlor-4'-(N-methylpiperazinyl)-thiocarbonylaminodiphenylamine.

12. The method according to claim 4 in which the ocarbonylamino-diphenylamine. 

1. AN ANTHELMINTIC COMPOSITION COMPRISING (1) AS ACTIVE INGREDIENT AN ANTHELMINTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. An anthelmintic composition comprising (1) as active ingredient an anthelmintically effective amount of a compound of the formula
 3. A method for combatting parasitic helminths which comprises administering to an animal suffering from the effects of said helminths an anthelmintically effective amount of a compound of the formula
 4. A method for combatting parasitic helminths which comprises applying to an animal suffering from the effects of said helminths an anthelmintically effective amount of a compound of the formula
 5. A method according to claim 4 in which R1 is hydrogen, chlorine, bromine, alkyl of from 1 to 4 carbon atoms or alkoxy of from 1 to 4 carbon atoms; R2 is hydrogen; and X is oxygen.
 6. The method according to claim 5 in which the compound is 4-Methoxy-4''-(N-methylpiperazinyl)-thiocarbonylaminodiphenylether.
 7. The method according to claim 5 in which the compound is 4-Nitro-4''-(N-methylpiperazinyl)-thiocarbonylaminodiphenylether.
 8. A method according to claim 4 in which R1 is hydrogen, chlorine, bromine, alkyl of from 1 to 4 carbon atoms or alkylthio of from 1 to 4 carbon atoms; R2 is hydrogen; X is imino; and R is alkyl of from 1 to 4 carbon atoms, phenyl or hydroxyalkyl of from 1 to 4 carbon atoms.
 9. The method according to claim 8 in which the compound is 4-Methylthio-4''-(N-methylpiperazinyl)-thiocarbonylamino-diphenylamine.
 10. The method according to claim 8 in which the compound is 4-ethyl-4''(N-methylpiperazinyl)-thiocarbonylaminodiphenylamine.
 11. The method according to claim 8 in which the compound is 4-Chlor-4''-(N-methylpiperazinyl)-thiocarbonylaminodiphenylamine.
 12. The method according to claim 4 in which the compound is 2, 4-dimethyl-4''-(N-ethylpiperazinyl)-thiocarbonylamino-diphenylamine. 